Although mu opioid receptor (MOP) agonists are the most commonly used opioids for the treatment of moderate to severe pain in the clinic, several side effects of MOP agonists limit their value as spinal analgesics. Research to identify novel analgesics with fewer side effects is pivotal to advancing the health care of humans. Scientists have discovered N/OFQ, a heptadecapeptide that is an endogenous ligand for the novel opioid receptors (now named NOP receptors). In particular, intrathecal administration of NOP agonists produced robust antinociceptive effects in animals under different pain modalities. More importantly, we have found that combinations of MOP agonists and NOP agonists have synergistic antinociceptive effects in the monkey nociceptive models. These exciting results prompt this proposal to evaluate a novel analog, BU10038, that has been developed and synthesized by Dr. Husbands in side-by-side comparisons with morphine in a number of assays in rhesus monkeys. BU10038 has binding affinities on both MOP and NOP receptors and displays partial agonist actions on both receptors. These monkey assays have been established specifically to reflect the therapeutic (spinal analgesia) and side effect (pruritus, vomitting, respiratory depression, hypotention, hypothermia and constipation) profile of opioid analgeiscs. In the first aim of this proposal, antinociceptive effects of BU10038 following intrathecal administration will be evaluated and determined with MOP and NOP antagonists. In the second aim, several assays will be conducted to establish the side effect/safety profile of intrathecal BU10038 as compared with that of morphine. The possibility that drugs with agonist actions at both receptors will be potent and effective spinal analgesics with reduced side effects encourages our pharmacological studies of BU10038. Our unique set of physiological and behavioral assays in conscious rhesus monkeys implanted with intrathecal catheters, in combination with the availability of a novel bifunctional MOP/NOP agonist, sets the stage for the identification of a breakthrough in the effective and safe spinal analgeisc in the future clinical application. RELEVANCE: The proposed research is relevant to public health because it could result in the identification of a spinal analgesic with promising therapeutic profile. Identification of a superir spinal analgesic with fewer side effects has long been a goal of pain management. Such a drug could profoundly impact the practice of spinal analgesia as well as substantially reduce the risks and concerns posed by the currently available mu opioid analgesics.